ArticleNature medicine2015
Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 161 citations in OpenAlex.
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- Selective small molecule targeting of KDM4 as a therapeutic strategy to reduce proliferation of acute myeloid leukaemia.British journal of haematology · 2026Article
- Chromatin-associated circRNA ciCRLF3(2) regulates cell differentiation blockage via activating non-homologous end joining-based DNA repair.Cell death and differentiation · 2026Article
- Augmented myeloablative conditioning with olaparib in allogeneic hematopoietic stem cell transplantation for relapsed/refractory RUNX1::RUNX1T1-positive acute myeloid leukemia.Frontiers in oncology · 2026Article
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- Significance of targeting DNMT3A mutations in AML.Annals of hematology · 2025Review
- Star wars against leukemia: attacking the clones.Leukemia · 2024Review
- Characterization of stem cell landscape and assessing the stemness degree to aid clinical therapeutics in hematologic malignancies.Scientific reports · 2024Article
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- Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia.Cancer medicine · 2024Review
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- High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.Nature communications · 2024Article
- Therapeutic targeting of PARP with immunotherapy in acute myeloid leukemia.Frontiers in pharmacology · 2024Review
- Targeting the DNA damage response in hematological malignancies.Frontiers in oncology · 2024Review
- Article
- Targetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia.Nature communications · 2023Article
- Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination-Deficient Leukemia Cells.Molecular cancer research : MCR · 2023Article
- Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.